The HOPE4MCI study: AGB101 treatment slows progression of entorhinal cortex atrophy in ε4 non-carriers with mild cognitive impairment due to Alzheimer's disease.

Introduction: Hippocampal hyperactivity is a hallmark of prodromal Alzheimer's disease (AD) that predicts progression in patients with amnestic mild cognitive impairment (aMCI). AGB101 is an extended-release formulation of levetiracetam in the dose range previously demonstrated to normalize hippocampal activity and improve cognitive performance in aMCI. The HOPE4MCI study was a 78-week trial to assess the progression of MCI due to AD.

The HOPE4MCI study: A randomized double-blind assessment of AGB101 for the treatment of MCI due to AD.

Introduction: In addition to the accumulation of amyloid plaques and neurofibrillary tangles, the presence of excess neural activity is a pathological hallmark of Alzheimer's disease (AD) and a prognostic indicator for progression of AD pathology and clinical/cognitive worsening in mild cognitive impairment due to Alzheimer's disease (MCI due to AD). The HOPE4MCI clinical study tested the efficacy of a therapeutic with demonstrated ability to normalize heightened neural activity in the hippocampus in a randomized controlled trial of 78 weeks duration in patients with MCI due to AD.

Methods: One hundred and sixty-four participants were randomized to placebo ( = 83) or AGB101 ( = 81), an extended-release formulation of low dose (220 mg) levetiracetam.

Object-place-context learning impairment correlates with spatial learning impairment in aged Long-Evans rats.

The hippocampal formation is vulnerable to the process of normal aging. In humans, the extent of this age-related deterioration varies among individuals. Long-Evans rats replicate these individual differences as they age, and therefore they serve as a valuable model system to study aging in the absence of neurodegenerative diseases.

Individual differences in age-related neurocognitive outcomes: within-subject assessment of memory for odors.

Cognitive decline is a common feature of aging, particularly in memory domains supported by the medial temporal lobe (MTL). The ability to identify intervention strategies to treat or prevent this decline is challenging due to substantial variability between adults in terms of age of onset, rate and severity of decline, and many factors that could influence cognitive reserve. These factors can be somewhat mitigated by use of within-subject designs.

mGluR-dependent plasticity in rodent models of Alzheimer's disease.

Long-term potentiation (LTP) and depression (LTD) are currently the most comprehensive models of synaptic plasticity models to subserve learning and memory. In the CA1 region of the hippocampus LTP and LTD can be induced by the activation of either NMDA receptors or mGluR5 metabotropic glutamate receptors. Alterations in either form of synaptic plasticity, NMDAR-dependent or mGluR-dependent, are attractive candidates to contribute to learning deficits in conditions like Alzheimer's disease (AD) and aging.

Loss of functional heterogeneity along the CA3 transverse axis in aging.

Age-related deficits in pattern separation have been postulated to bias the output of hippocampal memory processing toward pattern completion, which can cause deficits in accurate memory retrieval. Although the CA3 region of the hippocampus is often conceptualized as a homogeneous network involved in pattern completion, growing evidence demonstrates a functional gradient in CA3 along the transverse axis, as pattern-separated outputs (dominant in the more proximal CA3) transition to pattern-completed outputs (dominant in the more distal CA3). We examined the neural representations along the CA3 transverse axis in young (Y), aged memory-unimpaired (AU), and aged memory-impaired (AI) rats when different changes were made to the environment.

Lateral entorhinal cortex dysfunction in amnestic mild cognitive impairment.

The entorhinal cortex is the site of some of the earliest pathological changes in Alzheimer's disease, including neuronal, synaptic and volumetric loss. Specifically, the lateral entorhinal cortex shows significant accumulation of tau neurofibrillary tangles in the amnestic mild cognitive impairment (aMCI) phase of Alzheimer's disease. Although decreased entorhinal cortex activation has been observed in patients with aMCI in the context of impaired memory function, it remains unclear if functional changes in the entorhinal cortex can be localized to the lateral or medial entorhinal cortex.

Individual differences in neurocognitive aging in outbred male and female long-evans rats.

Individual differences in biology as well as experience and exposures throughout life may contribute risk or resilience to neurocognitive decline in aging. To investigate the role of sex as a biological variable in cognitive function due to normal aging, we used substantial cohorts of healthy male and female aged outbred rats maintained under similar conditions throughout life to assess whether both sexes display a similar distribution of individual differences in behavioral performance using a water maze task optimized to assess hippocampal-dependent cognition in aging. We found both aged male and female rats performed poorer than young adults overall, but with no performance differences between sex in either young adults or aged groups in memory probe tests.

All-or-none disconnection of pyramidal inputs onto parvalbumin-positive interneurons gates ocular dominance plasticity.

Disinhibition is an obligatory initial step in the remodeling of cortical circuits by sensory experience. Our investigation on disinhibitory mechanisms in the classical model of ocular dominance plasticity uncovered an unexpected form of experience-dependent circuit plasticity. In the layer 2/3 of mouse visual cortex, monocular deprivation triggers a complete, "all-or-none," elimination of connections from pyramidal cells onto nearby parvalbumin-positive interneurons (Pyr→PV).

Effect of aging differs for memory of object identity and object position within a spatial context.

There has been considerable focus on investigating age-related memory changes in cognitively healthy older adults, in the absence of neurodegenerative disorders. Previous studies have reported age-related domain-specific changes in older adults, showing increased difficulty encoding and processing object information but minimal to no impairment in processing spatial information compared with younger adults. However, few of these studies have examined age-related changes in the encoding of concurrently presented object and spatial stimuli, specifically the integration of both spatial and nonspatial (object) information.

Spatial learning in male and female Long-Evans rats.

Male and female Long-Evans rats were tested in the Morris water maze at 6 months of age. A place training procedure, in which rats learned the position of a camouflaged platform, was followed by cue training, in which rats escaped to a visible platform. No sex difference was found in place learning ability.

Heterogeneity of Age-Related Neural Hyperactivity along the CA3 Transverse Axis.

Age-related memory deficits are correlated with neural hyperactivity in the CA3 region of the hippocampus. Abnormal CA3 hyperactivity in aged rats has been proposed to contribute to an imbalance between pattern separation and pattern completion, resulting in overly rigid representations. Recent evidence of functional heterogeneity along the CA3 transverse axis suggests that proximal CA3 supports pattern separation while distal CA3 supports pattern completion.

Decreased investigatory head scanning during exploration in learning-impaired, aged rats.

"Head scanning" is an investigatory behavior that has been linked to spatial exploration and the one-trial formation or strengthening of place cells in the hippocampus. Previous studies have demonstrated that a subset of aged rats with normal spatial learning performance show head scanning rates during a novel, local-global cue-mismatch manipulation that are similar to those of young rats. However, these aged rats demonstrated different patterns of expression of neural activity markers in brain regions associated with spatial learning, perhaps suggesting neural mechanisms that compensate for age-related brain changes.

Using internal memory representations in associative learning to study hallucination-like phenomenon.

Studies of Pavlovian conditioning have enriched our understanding of how relations among events can adaptively guide behavior through the formation and use of internal mental representations. In this review, we illustrate how internal representations flexibly integrate new updated information in reinforcer revaluation to influence relationships to impact actions and outcomes. We highlight representation-mediated learning to show the similarities in properties and functions between internally generated and directly activated representations, and how normal perception of internal representations could contribute to hallucinations.

Afterhyperpolarization amplitude in CA1 pyramidal cells of aged Long-Evans rats characterized for individual differences.

Altered neural excitability is considered a prominent contributing factor to cognitive decline during aging. A clear example is the excess neural activity observed in several temporal lobe structures of cognitively impaired older individuals in rodents and humans. At a cellular level, aging-related changes in mechanisms regulating intrinsic excitability have been well examined in pyramidal cells of the CA1 hippocampal subfield.

Comparison of male and female patients with amnestic mild cognitive impairment: Hippocampal hyperactivity and pattern separation memory performance.

Introduction: Recent studies have suggested that sex confers a differential risk in the incidence and prevalence of Alzheimer's disease (AD) thought to be the result of the increased lifespan of women compared to men. However, other factors may contribute to risk beyond the effect of increased lifespan.

Methods: This study examined the role of sex in hippocampal hyperactivity localized to the dentate gyrus (DG)/CA3 subregion of the hippocampus and associated episodic memory impairment, considered a characteristic feature of AD in patients with amnestic mild cognitive impairment (aMCI).

Engagement of the Lateral Habenula in the Association of a Conditioned Stimulus with the Absence of an Unconditioned Stimulus.

Neurons in the lateral habenula (LHb) are activated by reward omission and inhibited by reward delivery-reward processing functions opposite those of midbrain dopaminergic neurons. To further explore this, we examined the role of the LHb in associating a conditioned stimulus (CS) with the absence of an unconditioned stimulus (US) in an appetitive Pavlovian-conditioning paradigm. Rats underwent training in which a CS (light) was either paired (100% CS-US contingency) or unpaired (0% CS-US contiguity and negative contingency) with an US (food).

Significance of inhibitory recruitment in aging with preserved cognition: limiting gamma-aminobutyric acid type A α5 function produces memory impairment.

Numerous aging studies have identified a shift in the excitatory/inhibitory (E/I) balance with heightened hippocampal neural activity associated with age-related memory impairment across species, including rats, monkeys, and humans. Neurobiological investigations directed at the hippocampal formation have demonstrated that unimpaired aged rats performing on par with young adult rats in a spatial memory task exhibit gene expression profiles, mechanisms for plasticity, and altered circuit/network function, which are distinct from younger rats. Particularly striking is a convergence of observational evidence that aged unimpaired rats augment recruitment of mechanisms associated with neural inhibition, a finding that may represent an adaptive homeostatic adjustment necessary to maintain neural plasticity and memory function in aging.

What are the threats to successful brain and cognitive aging?

The structure and function of the brain change over the life span. Aged brains often accumulate pathologic lesions, such as amyloid plaques and tau tangles, which lead to diminished cognitive ability in some, but not all, individuals. The basis of this vulnerability and resilience is unclear.

Reduced cognitive performance in aged rats correlates with increased excitation/inhibition ratio in the dentate gyrus in response to lateral entorhinal input.

Aging often impairs cognitive functions associated with the medial temporal lobe (MTL). Anatomical studies identified the layer II pyramidal cells of the lateral entorhinal cortex (LEC) as one of the most vulnerable elements within the MTL. These cells provide a major excitatory input to the dentate gyrus hippocampal subfield through synapses onto granule cells and onto local inhibitory interneurons, and a fraction of these contacts are lost in aged individuals with impaired learning.

Aged rats with intact memory show distinctive recruitment in cortical regions relative to young adults in a cue mismatch task.

Similar to elderly humans, aged Long-Evans rats exhibit individual differences in performance on tasks that critically depend on the medial temporal lobe memory system. Although reduced memory performance is common, close to half of aged rats in this outbred rodent population perform within the range of young subjects, exhibiting a stable behavioral phenotype that may signal a resilience to memory decline. Increasing evidence from research on aging in the Long-Evans study population supports the existence of adaptive neural change rather than avoidance of detrimental effects of aging on the brain, indicating a malleability of brain function over the life span that may preserve optimal function.

Aged rats with preserved memory dynamically recruit hippocampal inhibition in a local/global cue mismatch environment.

Similar to elderly humans, aged outbred Long-Evans rats exhibit individual differences in memory abilities, including a subset of aged rats that maintain memory function on par with young adults. Such individuals provide a basis for investigating mechanisms of resilience to age-related decline. The present study examined hippocampal gene expression in young adults and aged rats with preserved memory function under behavioral task conditions well established for assessing information processing central to the formation of episodic memory.

Cortical thickness atrophy in the transentorhinal cortex in mild cognitive impairment.

This study examines the atrophy rates of subjects with mild cognitive impairment (MCI) compared to controls in four regions within the medial temporal lobe: the transentorhinal cortex (TEC), entorhinal cortex (ERC), hippocampus, and amygdala. These regions were manually segmented and then corrected for undesirable longitudinal variability via Large Deformation Diffeomorphic Metric Mapping (LDDMM) based longitudinal diffeomorphometry. Diffeomorphometry techniques were used to compare thickness measurements in the TEC with the ERC.